Hyperparathyroidism jaw-tumor syndrome (HPT-JT) is a syndrome that predisposes individuals to the development of one or more benign or malignant parathyroid tumors, ossifying fibromas of the mandible and/or maxilla, benign or malignant uterine tumors and, less commonly, cystic kidney lesions, renal hamartomas or Wilm's tumors. Affected individuals may develop multiple primary parathyroid, jaw, uterine and/or kidney tumors over the course of their lifetime. Inactivating mutations of theHRPT2 tumor suppressor gene (also called CDC73), encoding parafibromin, were identified as the genetic cause of HPT-JT in the majority of affected kindreds. Subsequently, screens of sporadic parathyroid carcinomas, ossifying fibromas of the mandible and renal tumors revealed both germline and somatic mutations of HRPT2. The proposed studies are designed to address the mechanisms through which loss of Hrpt2/parafibromin promotes neoplasia in the parathyroid glands and jaws, in the pathophysiologically relevant experimental context of an intact animal. To study the pathophysiological consequences of knockout of Hrpt2 in vitro, genetically- engineered mice in which the Hrpt2 gene is flanked by two loxP sites have been generated and will be crossed with two different transgenic mouse strains, PTH-Cre and Wnt1-Cre. These crosses will result in offspring with Hrpt2 deletion in the parathyroid glands or mandible, respectively. Development of these two mouse models will provide a means for dissecting the molecular basis of HPT-JT, sporadic parathyroid tumors and ossifying jaw fibromas and may ultimately enable the development of new diagnostic and treatment strategies.